Our endogenous biological clocks control many key aspects of human physiology and behavior. Most cells in the body contain a circadian clock composed of interlocking transcriptional feedback loops and regulated protein turnover. Within the brain's hypothalamus, a network of neurons in the suprachiasmatic nuclei (SCN) form a master pacemaker responsible for receiving light input via the retina, driving the sleep-wake cycle, and coordinating circadian rhythms throughout the organism. This proposal aims to address the mechanisms by which extracellular signaling pathways impinge upon the core components of the mammalian circadian clock. We will also study how the clock globally modulates critical signaling pathways within the central nervous system and peripheral tissues. Given the broad impact of circadian control on major aspects of human behavior and physiology, the experiments in this proposal will substantially improve our understanding of the mechanisms underlying daily homeostasis and their associated pathologies. Little is known about how signaling events, such as those initiated by neurotransmitters or hormones, alter the circadian timing mechanism. Conversely, we also do not understand how clock components exert such wide ranging effects on physiology in different tissues. This proposal aims to further delineate the interactions between core clock components and cellular signals mediated by cAMP/CREB. Given the well established roles of cAMP/CREB signaling in a range of neuropsychiatric disorders, this work will have profound benefits by improving our understanding of these disorders. In addition, we wish to initiate a hypothesis-generating chemical biology approach to identifying compounds that will serve as chemical probes for revealing essential components of signaling pathways that affect clock function. Such novel cellular components may not be easily identified through genetics. Refined compounds identified from high throughput chemical screens will provide a chemical rationale for developing novel therapeutics for disorders of circadian signaling pathways, including sleep and mood disorders. PUBLIC HEALTH RELEVANCE: Our internal biological clocks control many important aspects of our physiology - from the sleep wake cycle to daily changes in blood pressure. Understanding how these clocks work inside cells provides the basis for developing new therapies to treat disorders as diverse as depression, insomnia and cardiovascular disease.